JP2763400B2 - Use of acetyl D-carnitine in therapeutic treatment of glaucoma - Google Patents

Description

The present invention relates to a novel therapeutic application of acetyl D-carnitine and its pharmacologically acceptable salts in the treatment of glaucoma. The invention further relates to suitable pharmaceutical compositions, especially eye drops.

The therapeutic use of acetyl D, L-carnitine and acetyl L-carnitine is already known. For example, US Pat. No. 4,194,006 describes the use of acetylcarnitine in the therapeutic treatment of anemia and myocardial arrhythmias. U.S. Pat. No. 4,343,816 describes the use of acetylcarnitine in the therapeutic treatment of functional peripheral vascular disease of the arteries, such as Raynaud's disease and amygdala. U.S. Pat. No. 4,346,107 describes the therapeutic utility of acetylcarnitine in the treatment of subjects affected by cerebral metabolic degeneration seen, for example, in senile and presenile dementia and Alzheimer's disease. However, there is no connection between the previously known therapeutic uses of L-carnitine and the uses forming the subject of the present invention. Furthermore, since the early 80's, the therapeutic use of L-carnitine has completely replaced the use of D, L-carnitine based on the finding that the D isomer exerts a detrimental antagonistic effect on L-carnitine. . It is therefore surprising that D-carnitine derivatives exert an effective therapeutic effect.

In fact, D-carnitine is a competitive inhibitor of carnitine-related enzymes such as carnitine acetyltransferase (CAT) and carnitine palmitoyltransferase (CPT), and D-carnitine depletes L-carnitine levels in cardiac and skeletal muscle It has been shown that it can. Of course, it is important to administer L-carnitine exclusively to the patient in the case of medical treatment of heart disease or usual hemodialysis treatment or blood lipid reduction, especially in the case of long-term treatment.

Finally, it should be noted that no literature teaching the use of carnitine or any derivative of carnitine in the ophthalmic field had been published prior to the filing of the present invention and that this is not related to the stereospecific form of the compound. is there.

Here, surprisingly, is a disease characterized by increased intraocular pressure, in which the use of acetyl D-carnitine and its pharmacologically acceptable salts causes a loss of vision ranging from slight loss of vision to complete blindness. It has been found useful in the therapeutic treatment of glaucoma. More specifically, acetyl D-carnitine and its pharmacologically acceptable salts are useful in the treatment of primary glaucoma (chronic open angle glaucoma or acute glaucoma or chronic closed angle glaucoma) or secondary glaucoma. .

Accordingly, the present invention contemplates the use of acetyl D-carnitine and its pharmaceutically acceptable salts for the manufacture of a pharmaceutical composition for the therapeutic treatment of glaucoma. In practice, approximately 1000-2000 mg daily dose of acetyl D-carnitine or one equivalent of one of its pharmaceutically acceptable salts is administered orally or parenterally. Alternatively, or preferably, concurrently with oral or parenteral treatment, acetyl D-carnitine 1
Administer an eye drop containing -10% w / v or an equivalent amount of a pharmaceutically acceptable salt thereof. Apply about 2-3 drops of eye drops 3-4 times a day.

The most suitable pharmaceutical composition for oral or parenteral administration is about 500-about 1000 mg of acetyl D-carnitine or one of its pharmacologically acceptable salts and is compatible with the active ingredient in a single dose A composition comprising a pharmacologically acceptable excipient. Examples of suitable compositions for one dose are described, for example, in US Pat. No. 4,464,393.

The composition of the eye drops consists of customary sterile isotonic solutions. Selection of the appropriate excipient is within the skill of those having ordinary skill in the pharmaceutical arts. For example, those used as excipients are sodium chloride, disodium phosphate, monosodium phosphate, benzalkonium chloride and ethyl alcohol. The composition is made up to volume with distilled water.

The activity of acetyl D-carnitine in the treatment of glaucoma has been demonstrated by pharmacological tests in in vivo and in vitro experimental models and clinical trials. Some of the above tests in the experimental model are described below.

Experimental model of cortisone-induced glaucoma Eight New Zealand rabbits, approximately 2 kg, were used. Venteran depot (betamethasone 4m) on the right eye of each animal
0.8 ml / week for 4 weeks. The left eye served as a control. Drugs administered subconjunctivally resulted in an increase in intraocular pressure at the first week, peaked at the second week, and remained constant until the fifth week.

During the third week of treatment with cortisone, the animals were divided into two groups of four each. The animals in Group 1 received 5% w / v acetyl D-carnitine eye drops in the right eye and two drops of saline in the left eye.

Intraocular pressure 1 hour before injection with Goldman tonometer 1,
Measurements were taken after 3, 5, 7, 12 and 24 hours.

A sharp decrease (Student's T test, p <0.05) was recorded in the intraocular pressure of eyes treated with acetyl D-carnitine that was statistically significant relative to eyes treated with saline.

Bolus administration of glucose-containing solution The experimental ocular hypertension model in rabbits was induced by bolus injection of a glucose-containing solution consisting of a rapid infusion of 15 ml per kilogram of body weight into a vein around the rabbit ear. Infusion produces high intraocular pressure and injection 10
Peaked after minutes and subsided after 40 minutes. There was no difference in the intraocular pressure of both eyes, and the intraocular pressure curves could be overlapped. To measure the anti-high pressure activity of acetyl D-carnitine, the basal pressure of either eye is measured 1 hour before injection, then 1 drop of medicine is poured into the right eye and 1 drop of saline is poured into the left eye No.
The pressure measurements were repeated immediately before injection and at 10, 20, and 40 minute intervals after injection.

Water bolus administration Anesthetized rabbit is orally-gastrically intubated and distilled water total volume 200m
l was administered. Intraocular pressure increased within about 1 hour and returned to normal after about 3 hours. The experimental range of this model was similar to that described above.

Administration of Alpha chymotrypsin Intra-ocular administration of alpha-chymotrypsin to rabbits (0.5 mg / animal / day) for 5 days resulted in an increase in intraocular pressure, which showed a chronic tendency. The experimental range of this model was similar to that described above.

In the aforementioned glaucoma test model, the effect of administration of acetyl D-carnitine on intraocular pressure was evaluated with a pneumatic tonometer and further controlled with a non-latency tonometer. Recordings were performed at standard time for acute glaucoma models and every 12 hours for chronic models.

Claims (7)

(57) [Claims] (1) A pharmaceutical composition for therapeutic treatment of glaucoma, comprising acetyl D-carnitine or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The pharmaceutical composition according to claim 1, which is suitable for oral or parenteral administration containing 1000-2000 mg / day of acetyl D-carnitine or an equivalent amount of a pharmaceutically acceptable salt thereof. . 3. A pharmaceutical composition for the therapeutic treatment of glaucoma, comprising acetyl D-carnitine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient as the only active ingredients. 4. The method according to claim 1, which is suitable for oral administration.
4. The pharmaceutical composition according to any one of 3. 5. The method according to claim 1, which is suitable for parenteral administration.
The pharmaceutical composition according to any one of claims 1 to 3. 6. The pharmaceutical composition according to claim 4, which is in a unit dosage form containing 250 to 500 mg of acetyl D-carnitine or an equivalent amount of a pharmaceutically acceptable salt thereof. 7. A method for treating glaucoma comprising 1-10% w / v acetyl D-carnitine or one equivalent of a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable liquid excipient. Eye drops.